title: Activation of peroxisome proliferator-activated receptor gamma by rosiglitazone increases sirt6 expression and ameliorates hepatic steatosis in rats.
abstract: BACKGROUND
  Sirt6 has been implicated in the regulation of hepatic lipid metabolism and the development of hepatic steatosis. The aim of this study was to address the potential role of Sirt6 in the protective effects of rosiglitazone (RGZ) on hepatic steatosis.
  
  
  METHODS
  To investigate the effect of RGZ on hepatic steatosis, rats were treated with RGZ (4 mg·kg⁻¹·day⁻¹) by stomach gavage for 6 weeks. The involvement of Sirt6 in the RGZ's regulation was evaluated by Sirt6 knockdown in AML12 mouse hepatocytes.
  
  
  RESULTS
  RGZ treatment ameliorated hepatic lipid accumulation and increased expression of Sirt6, peroxisome proliferator-activated receptor gamma coactivtor-1-α (Ppargc1a/PGC1-α) and Forkhead box O1 (Foxo1) in rat livers. AMP-activated protein kinase (AMPK) phosphorylation was also increased by RGZ, accompanied by alterations in phosphorylation of LKB1. Interestingly, in free fatty acid-treated cells, Sirt6 knockdown increased hepatocyte lipid accumulation measured as increased triglyceride contents (p = 0.035), suggesting that Sirt6 may be beneficial in reducing hepatic fat accumulation. In addition, Sirt6 knockdown abolished the effects of RGZ on hepatocyte fat accumulation, mRNA and protein expression of Ppargc1a/PGC1-α and Foxo1, and phosphorylation levels of LKB1 and AMPK, suggesting that Sirt6 is involved in RGZ-mediated metabolic effects.
  
  
  CONCLUSIONS
  Our results demonstrate that RGZ significantly decreased hepatic lipid accumulation, and that this process appeared to be mediated by the activation of the Sirt6-AMPK pathway. We propose Sirt6 as a possible therapeutic target for hepatic steatosis.
authors.affiliation: Diabetes Research Institute, Sungkyunkwan University School of Medicine, Kangbuk Samsung Hospital, Seoul, Korea.
authors.forename: Soo Jin
authors.initials: SJ
authors.lastname: Yang
authors.forename: Jung Mook
authors.initials: JM
authors.lastname: Choi
authors.forename: Seoung Wan
authors.initials: SW
authors.lastname: Chae
authors.forename: Won Jun
authors.initials: WJ
authors.lastname: Kim
authors.forename: Se Eun
authors.initials: SE
authors.lastname: Park
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Rhee
authors.forename: Won Young
authors.initials: WY
authors.lastname: Lee
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Oh
authors.forename: Sung Woo
authors.initials: SW
authors.lastname: Park
authors.forename: Sun Woo
authors.initials: SW
authors.lastname: Kim
authors.forename: Cheol-Young
authors.initials: CY
authors.lastname: Park
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D005234:Fatty Liver / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D000960:Hypolipidemic Agents / Q000494:pharmacology; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D051381:Rats; D020334:Rats, Inbred OLETF; D020318:Rats, Long-Evans; D000077154:Rosiglitazone; D037761:Sirtuins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D000960:Hypolipidemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C501860:Sirt6 protein, mouse; D037761:Sirtuins; C560607:sirtuin 6, rat